1. Field of the Invention
The present invention relates generally to novel peptides of formula I R.sup.1 -His-Asp-Glu-Ala-R, wherein R.sup.1 is Ala-Gln and R is
Gln-Gln-Asn-Ala-Phe-Tyr-Gln-Val-Leu-Asn-Met-Pro-Asn-Leu-Asn-Ala-Asp-Gln-Arg -Asn-Gly-Phe-Ile-Gln-Ser-Leu-Lys-Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Val-Leu-Gl y-Glu-Ala-Gln-Lys-Leu-Asn-Asp-Ser-Gln-Ala-Pro-Lys PA1 Gln-Gln-Asn-Ala-Phe-Tyr-Gln-Val-Leu-Asn-Met-Pro-Asn-Leu-Asn-Ala-Asp-Gln-Arg -Asn-Gly-Phe-Ile-Gln-Ser-Leu-Lys-Asp- Asp-Pro-Ser-Gln-Ser-Ala-Asn-Val-Leu-Gly-Glu-Ala-Gln-Lys-Leu-Asn-Asp-Ser-Gl n-Ala-Pro-Lys PA1 Ala-Gln-His-Asp-Glu-Ala-Gln-Gln-Asn-Ala-Phe-Tyr-Gln-Val-Leu- Asn-Met-Pro-Asn-Leu-Asn-Ala-Asp-Gln-Arg-Asn-Gly-Phe-Ile-Gln- Ser-Leu-Lys-Asp-Asp-Pro-Ser-Gln-Ser-Ala-Asn-Val-Leu-Gly-Glu- Ala-Gln-Lys-Leu-Asn-Asp-Ser-Gln-Ala-Pro, pX-3' (corresponding to the 55 N-terminal amino acid residues in region of SpA), PA1 Ala-Gln-His-Asp-Glu-Ala-Gln-Gln-Asn-Ala-Phe-Tyr-Gln-Val-Leu- Asn-Met-Pro-Asn-Leu-Asn-Ala-Asp-Gln-Arg, pX-1' (corresponding to the first 25 amino acid residues in region E), PA1 Ala-Gln-His-Asp-Glu-Ala-Gln-Gln-Asn-Ala-Phe-Tyr-Gln-Val-Leu- Asn-Met-Pro-Asn-Leu, pX-2' (corresponding to the first 20 amino acid residues in region E), PA1 Gln-His-Asp-Glu-Ala-Gln-Gln-Asn-Ala-Phe-Tyr-Gln-Val-Leu-Asn- Met-Pro-Asn-Leu, pX-4' (corresponding to amino acid residues 2 to 20 in region E), and PA1 His-Asp-Glu-Ala-Gln-Gln-Asn-Ala-Phe-Tyr-Gln-Val-Leu-Asn-Met- Pro-Asn-Leu, pX-5' (corresponding to amino acids 3 to 20 in region E).
and wherein at least one, more or all of the amino acid residues in R.sup.1, R, or both is omitted; and physiologically compatible salts or esters thereof. These peptides exhibit interesting and surprising pharmacological properties in that they possess the ability to augment cell-mediated cytotoxity. The present invention therefore also relates to pharmaceutical compositions containing at least one of these peptides, their use as a medicament, e.g. an anticancer or antiviral agent, and methods for augmenting cell-mediated cytotoxicity in humans and other mammals.
In the following specification and claims the nomenclature used herein complies with that stated in J.Biol.Chem 247 (1972), 977 et seq.
2. Brief Description of the Background Art
Cancers and viral infections are serious conditions and until now no medicament has been found which can be used against all cancers or viral infections without side effects.
Natural killing (hereinafter NK) and antibody-dependent cellular cytotoxicity (hereinafter ADCC) are known examples of immunological defense mechanisms against cancer and viral infections. Several studies have indicated the relation between these types of cellular cytotoxic reactions and defense mechanisms against cancer as well as against viral infections. Therefore, stimulation of NK- and/or ADCC-activity as well as other mechanisms of cellular cytotoxicity (hereinafter collectively designated cellular killing (K-cell activity)) in vivo is believed to be of great relevance for the treatment of cancers and viral infections.
It has been demonstrated that one group of proteins, i.e. the interferons, stimulates these types of reactions. It is also known that certain other peptides and proteins stimulate K-cell activities. The lymphokine interleukin-2 has been indicated as particularly important for the stimulation of K-cell activity, and the augmentation of K-cell activity by lymphokines after stimulation for 3-5 days is often referred to as lymphokine activated killing (hereinafter LAK) and stimulated cells are referred to as lymphokine activated killer cells (hereinafter LAK-cells).
It is known that protein A from Staphylococcus aureus stimulates K-cell activities.
It is further known that S. aureus protein A (hereinafter SpA) has a number of other immunologic properties, including activation of the complement system, polyclonal stimulation of B- and T-lympocytes, polyclonal activation of antibody synthesis and interferon induction.
These properties of SpA have led to a great deal of interest in the use of SpA as an immunologic reagent, and it is most desirable to find a way to exploit the useful properties of SpA without triggering the more adverse properties of this protein.
SpA cannot be employed directly in vivo since it may cause hypersensitive reactions (probably due to its binding to the Fc part of immunoglobulins with subsequent activation of complement etc.). Various preparations of the complete SpA molecule have, however, been utilized either for extracorporeal large-scale plasma adsorption (J. Balint jr. et al.: Cancer Research 44 (1984), 734-743), which was interpreted in terms of interaction with immunoglobulins in immune complexes, or for intravenous infusion in animals (H.D. Harper et al.: Cancer 55 (1985), 1863-1867) with beneficial results.
Protein A from S. aureus is a protein of which the NH.sub.2 -terminal part contains five homologous units comprising from 56 to 61 amino acids each, and the COOH-terminal part contains several repeats of an octapeptide (cf. Uhlen M. et al.: J.Biol.Chem. 259, 3 (1984), 1695-1702).
The five homologous regions in the N-terminal part are usually designated E, D, A, B, and C regions, and the C-terminal part is designated the X region.
The structure of SpA has been extensively studied and is described in a number of publications such as WO No. 8400773, WO No. 8400774, WO No. 840310 all to Pharmacia AB, and EP No. A2 107,509 to Repligen Corp. whereto reference is made.
The results obtained in studies performed by J. Sjodahl and G. Moller (Scand.J.Immunol. 10 (1979), 593-596) and Olinescu et al. (Immunol.Letters 6 (1983), 231-237) have been interpreted as indicating that the active part of the SpA molecule should be in the so-called X region, the C-terminally located portion of the molecule.